TLR Transduction of Dysbiotic Pelvic Pain

生态失调性盆腔疼痛的 TLR 转导

• 批准号: 10737191
• 负责人: David J Klumpp
• 金额: $ 58.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737191
• 关键词: Ablation; Acute Pain; Biological Markers; Biological Process; Cells; Chronic Prostatitis; Circulation; Clinic; Clinical; Cues; Data; Development; Diagnosis; Disease; Endotoxins; Etiology; Exhibits; Female; Fostering; Future; Gene Expression; Genetic; Genetic Predisposition to Disease; Immune; In Vitro; Infection; Interstitial Cystitis; Knockout Mice; Leaky Gut; Mediating; Mediator; Microglia; Modeling; Morbidity - disease rate; Morphology; Mus; Neurons; Pain; Pathogenesis; Pathogenicity; Patients; Pelvic Pain; Phenotype; Play; Probiotics; Reporting; Rodent; Rodent Model; Role; Serum; Signal Transduction; Site; Symptoms; TLR4 gene; Testing; Toll-like receptors; Transducers; attenuation; chronic pain; chronic pelvic pain; clinically relevant; cognitive function; conditional knockout; dysbiosis; effective therapy; fecal transplantation; genetic approach; glial activation; gut dysbiosis; gut microbiota; in vivo; innovation; men; microbial; microbial products; microbiome; microbiota; mouse model; novel; pain behavior; pain patient; pain score; pharmacologic; pre-clinical; probiotic therapy; response; targeted treatment; transcriptome sequencing; treatment strategy; urologic; urologic chronic pelvic pain syndrome

Chronic pelvic pain is debilitating and afflicts millions of patients in the U.S., yet pelvic pain etiologies and effective therapies remain elusive. Microglia are CNS immune cells that play significant roles in pain and are poised to respond to changes in microbiota, yet the roles of microglia in pelvic pain are not fully described. Similarly, the microbiome influences many biological processes and is recently appreciated to modulate pain, and we have identified gut dysbiosis in pelvic pain patients and clinically relevant mouse models of pelvic pain. Microglia can transduce microbiome signals by virtue of Toll-like receptors, but their roles in mediating pelvic pain modulation by microbiota have not been explored. Here, we will evaluate the role of microglia responses to microbiota in clinically-relevant models of pelvic pain. We hypothesize that TLR4 mediates microglial responses to gut microbiota. We will test this hypothesis using two clinically relevant mouse models of distinct underlying mechanisms that mimic postulated etiologies of urologic pelvic pain, an infection model and a genetic susceptibility model. In Aim 1, we will quantify the role of microglia in rodent correlates of pain responses and cognitive function and define microglial phenotypes. In Aim 2, we will define the role of TLR4 in microglia- mediated pain. And in Aim 3, we will examine microglial responses to microbiota. Together, these rigorous and innovative studies will provide the first characterization of TLR4 in microglia- dependent pelvic pain responses to microbiota and thus pave the way for future probiotic strategies for the treatment of urologic chronic pelvic pain.

慢性骨盆疼痛令人衰弱，在美国遭受了数百万患者的痛苦，但骨盆疼痛 病因和有效疗法仍然难以捉摸。小胶质细胞是CNS免疫细胞 在疼痛中的重要作用，并有望应对微生物群的变化，但是 骨盆疼痛中的小胶质细胞未充分描述。同样，微生物组会影响许多 生物学过程，最近对调节疼痛表示赞赏，我们已经确定了肠道 骨盆疼痛患者的营养不良和骨盆疼痛的临床相关小鼠模型。小胶质细胞可以 通过类似收费的受体转导微生物组信号，但它们在介导骨盆中的作用 尚未探索微生物群的疼痛调节。在这里，我们将评估 骨盆疼痛模型中对菌群的小胶质细胞反应。我们假设 TLR4介导了对肠道微生物群的小胶质细胞反应。我们将使用两个 模仿假设的不同潜在机制的临床相关小鼠模型 泌尿科骨盆疼痛的病因，感染模型和遗传敏感性模型。目标 1，我们将量化小胶质细胞在啮齿动物相关性和认知的啮齿动物相关性中的作用 功能并定义小胶质表型。在AIM 2中，我们将定义TLR4在小胶质细胞中的作用 介导的疼痛。在AIM 3中，我们将检查对微生物群的小胶质响应。在一起，这些 严格而创新的研究将提供小胶质细胞中TLR4的首次表征 依赖性骨盆疼痛对微生物群的反应，从而为将来的益生菌铺平了道路 治疗泌尿科慢性骨盆疼痛的策略。